bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2022‒08‒14
twelve papers selected by
Gabriela Da Silva Xavier
University of Birmingham

  1. Prog Brain Res. 2022 ;pii: S0079-6123(22)00066-8. [Epub ahead of print]273(1): 97-116
      Over the last decades remarkable advances have been made in the understanding of the photobiology of circadian rhythms. The identification of a third photoreceptive system in the mammalian eye, in addition to the rods and cones that mediate vision, has transformed our appreciation of the role of light in regulating physiology and behavior. These photosensitive retinal ganglion cells (pRGCs) express the blue-light sensitive photopigment melanopsin and project to the suprachiasmatic nuclei (SCN)-the master circadian pacemaker-as well as many other brain regions. Much of our understanding of the fundamental mechanisms of the pRGCs, and the processes that they regulate, comes from mouse and other rodent models. Here we describe the contribution of rodent models to circadian photobiology, including both their strengths and limitations. In addition, we discuss how an appreciation of both rodent and human data is important for translational circadian photobiology. Such an approach enables a bi-directional flow of information whereby an understanding of basic mechanisms derived from mice can be integrated with studies from humans. Progress in this field is being driven forward at several levels of analysis, not least by the use of personalized light measurements and photoreceptor specific stimuli in human studies, and by studying the impact of environmental, rather than laboratory, lighting on different rodent models.
    Keywords:  Circadian; Light; Melanopsin; Mouse models; Photobiology; Translation
  2. Proc Natl Acad Sci U S A. 2022 Aug 16. 119(33): e2204470119
      Most mammalian cells have an intrinsic circadian clock that coordinates metabolic activity with the daily rest and wake cycle. The circadian clock is known to regulate cell differentiation, but how continuous daily oscillations of the internal clock can control a much longer, multiday differentiation process is not known. Here, we simultaneously monitor circadian clock and adipocyte-differentiation progression live in single cells. Strikingly, we find a bursting behavior in the cell population whereby individual preadipocytes commit to differentiate primarily during a 12-h window each day, corresponding to the time of rest. Daily gating occurs because cells irreversibly commit to differentiate within only a few hours, which is much faster than the rest phase and the overall multiday differentiation process. The daily bursts in differentiation commitment result from a differentiation-stimulus driven variable and slow increase in expression of PPARG, the master regulator of adipogenesis, overlaid with circadian boosts in PPARG expression driven by fast, clock-driven PPARG regulators such as CEBPA. Our finding of daily bursts in cell differentiation only during the circadian cycle phase corresponding to evening in humans is broadly relevant, given that most differentiating somatic cells are regulated by the circadian clock. Having a restricted time each day when differentiation occurs may open therapeutic strategies to use timed treatment relative to the clock to promote tissue regeneration.
    Keywords:  adipogenesis; cell differentiation; cell-fate decision; circadian rhythms; positive feedback
  3. J Nutr Biochem. 2022 Aug 05. pii: S0955-2863(22)00189-9. [Epub ahead of print] 109121
      Fasting/feeding cycles regulate clock-lipid-bile acid (BA) metabolic homeostasis, and gut microbiota also participates in connecting circadian rhythms with BA metabolism. To investigate the cyclical nature of microbial-metabolism-host interactions, sixty male C57BL/6 mice were randomized into three feeding regimens with a chow diet: 24 h ad libitum (AC), 12 h nighttime feeding (NC) or 12 h daytime feeding (DC). Five weeks later, the mice were sacrificed at six-hour intervals over 24 hours. Daytime feeding abolished hepatic rhythmic expressions of Per1, Cry1/2 and Rev-erbα or changed the acrophase of Clock, Bmal1 and Per2, also the rhythmic expression of genes Hsl, Fas, Acc, Srebp-1c in lipid homeostasis and Cyp7a1, Cyp7b1, Cyp8b1, Lrh-1 and Shp in bile acid metabolism compared with their ad libitum and dark-fed companions. Furthermore, daytime feeding upregulated the levels of fecal primary BA, secondary BA and unconjugated BA at ZT0 and decreased their levels at ZT12. Meanwhile, daytime feeding altered the diversity of gut microbiota and microbiota compositions, with obviously higher abundance of Firmicutes and F/B ratio, and significantly lower abundance of Verrucomicrobia, as well as altered fluctuations of Akkermansia, Lactobacillus and Parabacteroides. In conclusion, shifting food intake to the rest phase caused a desynchronization in the liver between circadian rhythm and metabolism, as well as abnormal circadian variations in fecal BA profiles and gut microbiota.
    Keywords:  bile acid metabolism; gut microbiota; lipid metabolism; liver clock; mistimed feeding
  4. Prog Brain Res. 2022 ;pii: S0079-6123(22)00132-7. [Epub ahead of print]273(1): 171-180
      Light is the preeminent external influence in determining the position of the internal circadian clock relative to the outside world. In this chapter, we discuss the different parameters of light that impact how it influences the human circadian clock. We detail how the timing (phase), intensity, duration and temporal structure, and spectral composition all can modulate the impact of light on both the timing of the circadian clock as well as its amplitude. The neurobiological underpinnings of the system are briefly discussed in the context of understanding how light can evoke its observed effects on the circadian clock.
    Keywords:  Amplitude; Circadian; Dose response; Human; Intensity; Light; Mathematical modeling; Phase; Spectral sensitivity
  5. Commun Biol. 2022 Aug 06. 5(1): 792
      Circadian clocks in the mammalian retina regulate a diverse range of retinal functions that allow the retina to adapt to the light-dark cycle. Emerging evidence suggests a link between the circadian clock and retinopathies though the causality has not been established. Here we report that clock genes are expressed in the mouse embryonic retina, and the embryonic retina requires light cues to maintain robust circadian expression of the core clock gene, Bmal1. Deletion of Bmal1 and Per2 from the retinal neurons results in retinal angiogenic defects similar to when animals are maintained under constant light conditions. Using two different models to assess pathological neovascularization, we show that neuronal Bmal1 deletion reduces neovascularization with reduced vascular leakage, suggesting that a dysregulated circadian clock primarily drives neovascularization. Chromatin immunoprecipitation sequencing analysis suggests that semaphorin signaling is the dominant pathway regulated by Bmal1. Our data indicate that therapeutic silencing of the retinal clock could be a common approach for the treatment of certain retinopathies like diabetic retinopathy and retinopathy of prematurity.
  6. Prog Brain Res. 2022 ;pii: S0079-6123(22)00137-6. [Epub ahead of print]273(1): 145-169
      Daily changes in ambient illumination act as important time of day cues which are pivotal for aligning internal circadian clocks to external time. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), generally considered specialized for encoding light intensity (irradiance), are critical to this photoentrainment process. However, ipRGCs also convey information from conventional photoreceptor cells, the rods and cones. Here we review data from animal studies identifying the nature and roles of rod and cone signaling to the suprachiasmatic nucleus (SCN) circadian clock including evidence that visual features other than irradiance (color, spatiotemporal variations in light intensity) may influence photoentrainment or other SCN-dependent functions. Finally we consider the extent to which these findings from animal studies might similarly apply to human circadian function.
    Keywords:  Color; Cones; Humans; Irradiance; Melanopsin; Photoentrainment; Rodents; Rods; Spatiotemporal variation
  7. Nutrients. 2022 Jul 29. pii: 3136. [Epub ahead of print]14(15):
      Obesity and other metabolic diseases are major public health issues that are particularly prevalent in industrialized societies where circadian rhythmicity is disturbed by shift work, jet lag, and/or social obligations. In mammals, daylight entrains the hypothalamic suprachiasmatic nucleus (SCN) to a ≈24 h cycle by initiating a transcription/translation feedback loop (TTFL) of molecular clock genes. The downstream impacts of the TTFL on clock-controlled genes allow the SCN to set the rhythm for the majority of physiological, metabolic, and behavioral processes. The TTFL, however, is ubiquitous and oscillates in tissues throughout the body. Tissues outside of the SCN are entrained to other signals, such as fed/fasting state, rather than light input. This system requires a considerable amount of biological flexibility as it functions to maintain homeostasis across varying conditions contained within a 24 h day. In the face of either circadian disruption (e.g., jet lag and shift work) or an obesity-induced decrease in metabolic flexibility, this finely tuned mechanism breaks down. Indeed, both human and rodent studies have found that obesity and metabolic disease develop when endogenous circadian pacing is at odds with the external cues. In the following review, we will delve into what is known on the circadian rhythmicity of nutrient metabolism and discuss obesity as a circadian disease.
    Keywords:  circadian rhythms; metabolism; molecular clock; obesity
  8. Prog Brain Res. 2022 ;pii: S0079-6123(22)00138-8. [Epub ahead of print]273(1): 49-69
      Daily rhythms in behavior and physiology are programmed by a hierarchical group of biological clocks widely distributed in tissues and synchronized by the environmental day/night cycle. The retina is a remarkable model of circadian clock because it gathers photoreception, self-sustained oscillator function and physiological outputs within the same tissue. This clock plays a crucial function in adapting retinal physiology and visual function to the day/night changes and by regulating processes that are directly linked to retinal survival and phototoxicity. This article provides a comprehensive review of retinal circadian rhythms in vertebrates. Based on clock gene/protein expression, studies have shown that different cells within the retina are capable of generating sustained oscillations. However, this expression is divergent across vertebrate retinas with photoreceptors described as the primary site of rhythm generation in amphibians while in mammals, the current prevailing view is that each cell expresses the molecular clock machinery. First, we will present the molecular clock mechanisms at the origin of circadian rhythms, the retinal clock targets and then provide recent data about the mechanisms of light synchronization in an attempt to shed light on the role of the retinal clock in vertebrates.
    Keywords:  Circadian rhythms; Clock gene expression; Dopamine; Light; Melatonin; Photoreceptor; Retina
  9. Contemp Clin Trials. 2022 Aug 04. pii: S1551-7144(22)00198-7. [Epub ahead of print]120 106872
      Re-aligning eating patterns with biological rhythm can reduce the burden of metabolic syndrome in older adults with overweight or obesity. Time-restricted eating (TRE) has been shown to result in weight loss and improved cardiometabolic health while being less challenging than counting calories. The New York Time-Restricted EATing study (NY-TREAT) is a two-arm, randomized clinical trial (RCT) that aims to examine the efficacy and sustainability of TRE (eating window ≤10 h/day) vs. a habitual prolonged eating window (HABIT, ≥14 h/day) in metabolically unhealthy midlife adults (50-75 years) with overweight or obesity and prediabetes or type 2 diabetes (T2D). Our primary hypothesis is that the TRE will result in greater weight loss compared to HABIT at 3 months. The efficacy of the TRE intervention on body weight, fat mass, energy expenditure, and glucose is tested at 3 months, and the sustainability of its effect is measured at 12 months, with ambulatory assessments of sleep and physical activity (ActiGraph), eating pattern (smartphone application), and interstitial glucose (continuous glucose monitoring). The RCT also includes state-of-the-art measurements of body fat (quantitative magnetic resonance), total energy expenditure (doubly-labelled water), insulin secretion, insulin resistance, and glucose tolerance. Adherence to self-monitoring and reduced eating window are monitored remotely in real-time. This RCT will provide further insight into the effects of TRE on cardiometabolic health in individuals with high metabolic risk. Sixty-two participants will be enrolled, and with estimated 30% attrition, 42 participants will return at 12 months. This protocol describes the design, interventions, methods, and expected outcomes. Clinical trial registration:NCT04465721 IRB: AAAS7791.
    Keywords:  Continuous glucose monitoring system; Diabetes; Doubly labelled water; Glucose; Meal timing; Prediabetes; Time-restricted eating
  10. Front Endocrinol (Lausanne). 2022 ;13 863224
      Background: Inadequate sleep is associated with many detrimental health effects, including increased risk of developing insulin resistance and type 2 diabetes. These effects have been associated with changes to the skeletal muscle transcriptome, although this has not been characterised in response to a period of sleep restriction. Exercise induces a beneficial transcriptional response within skeletal muscle that may counteract some of the negative effects associated with sleep restriction. We hypothesised that sleep restriction would down-regulate transcriptional pathways associated with glucose metabolism, but that performing exercise would mitigate these effects.Methods: 20 healthy young males were allocated to one of three experimental groups: a Normal Sleep (NS) group (8 h time in bed per night (TIB), for five nights (11 pm - 7 am)), a Sleep Restriction (SR) group (4 h TIB, for five nights (3 am - 7 am)), and a Sleep Restriction and Exercise group (SR+EX) (4 h TIB, for five nights (3 am - 7 am) and three high-intensity interval exercise (HIIE) sessions (performed at 10 am)). RNA sequencing was performed on muscle samples collected pre- and post-intervention. Our data was then compared to skeletal muscle transcriptomic data previously reported following sleep deprivation (24 h without sleep).
    Results: Gene set enrichment analysis (GSEA) indicated there was an increased enrichment of inflammatory and immune response related pathways in the SR group post-intervention. However, in the SR+EX group the direction of enrichment in these same pathways occurred in the opposite directions. Despite this, there were no significant changes at the individual gene level from pre- to post-intervention. A set of genes previously shown to be decreased with sleep deprivation was also decreased in the SR group, but increased in the SR+EX group.
    Conclusion: The alterations to inflammatory and immune related pathways in skeletal muscle, following five nights of sleep restriction, provide insight regarding the transcriptional changes that underpin the detrimental effects associated with sleep loss. Performing three sessions of HIIE during sleep restriction attenuated some of these transcriptional changes. Overall, the transcriptional alterations observed with a moderate period of sleep restriction were less evident than previously reported changes following a period of sleep deprivation.
    Keywords:  circadian rhythm; high-intensity interval exercise (HIE); inflammation; mitochondria; skeletal muscle; sleep loss; sleep restriction; transcriptomics
  11. Front Neurosci. 2022 ;16 907508
      Epidemiological and experimental evidence recognize a relationship between sleep-wake cycles and adiposity levels, but the mechanisms that link both are not entirely understood. Adipose tissue secretes adiponectin and leptin hormones, mainly involved as indicators of adiposity levels and recently associated to sleep. To understand how two of the main adipose tissue hormones could influence sleep-wake regulation, we evaluated in male rats, the effect of direct administration of adiponectin or leptin in the ventrolateral preoptic nuclei (VLPO), a major area for sleep promotion. The presence of adiponectin (AdipoR1 and AdipoR2) and leptin receptors in VLPO were confirmed by immunohistochemistry. Adiponectin administration increased wakefulness during the rest phase, reduced delta power, and activated wake-promoting neurons, such as the locus coeruleus (LC), tuberomammillary nucleus (TMN) and hypocretin/orexin neurons (OX) within the lateral hypothalamus (LH) and perifornical area (PeF). Conversely, leptin promoted REM and NREM sleep, including increase of delta power during NREM sleep, and induced c-Fos expression in VLPO and melanin concentrating hormone expressing neurons (MCH). In addition, a reduction in wake-promoting neurons activity was found in the TMN, lateral hypothalamus (LH) and perifornical area (PeF), including in the OX neurons. Moreover, leptin administration reduced tyrosine hydroxylase (TH) immunoreactivity in the LC. Our data suggest that adiponectin and leptin act as hormonal mediators between the status of body energy and the regulation of the sleep-wake cycle.
    Keywords:  VLPO; circadian misalignment; hypothalamus; metabolism; obesity; sleep-wake; timing of food intake
  12. Nutrients. 2022 Jul 28. pii: 3113. [Epub ahead of print]14(15):
      This paper discusses the effect of chrononutrition on the regulation of circadian rhythms; in particular, that of chocolate on the resynchronization of the human internal biological central and peripheral clocks with the main external synchronizers, light-dark cycle and nutrition-fasting cycle. The desynchronization of internal clocks with external synchronizers, which is so frequent in our modern society due to the tight rhythms imposed by work, social life, and technology, has a negative impact on our psycho-physical performance, well-being, and health. Taking small amounts of chocolate, in the morning at breakfast at the onset of the active phase, helps speed up resynchronization time. The high flavonoid contents in chocolate promote cardioprotection, metabolic regulation, neuroprotection, and neuromodulation with direct actions on brain function, neurogenesis, angiogenesis, and mood. Although the mechanisms of action of chocolate compounds on brain function and mood as well as on the regulation of circadian rhythms have yet to be fully understood, data from the literature currently available seem to agree in suggesting that chocolate intake, in compliance with chrononutrition, could be a strategy to reduce the negative effects of desynchronization. This strategy appears to be easily implemented in different age groups to improve work ability and daily life.
    Keywords:  brain function; chocolate; chrononutrition; circadian rhythms; flavonoid; mood